CN111875721B - Modified polyacrylic acid copolymer and preparation method and application thereof - Google Patents
Modified polyacrylic acid copolymer and preparation method and application thereof Download PDFInfo
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- CN111875721B CN111875721B CN202010725738.XA CN202010725738A CN111875721B CN 111875721 B CN111875721 B CN 111875721B CN 202010725738 A CN202010725738 A CN 202010725738A CN 111875721 B CN111875721 B CN 111875721B
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- polyacrylic acid
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08F—MACROMOLECULAR COMPOUNDS OBTAINED BY REACTIONS ONLY INVOLVING CARBON-TO-CARBON UNSATURATED BONDS
- C08F8/00—Chemical modification by after-treatment
- C08F8/14—Esterification
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
Abstract
The invention provides a modified polyacrylic acid copolymer and a preparation method and application thereof. The copolymer has good biocompatibility, amphipathy and adjustable pH responsiveness, and can be used for loading Chinese herbal medicines such as myricetin and the like and realizing drug release under different pH values.
Description
Technical Field
The invention belongs to the technical field of modified copolymers, and particularly relates to a modified polyacrylic copolymer and a preparation method and application thereof.
Background
The polymer drug delivery system is characterized in that a polymer carrier is used for entrapping, adsorbing or chemically connecting drugs, the drugs are delivered to a focus part by using the characteristics of the drug carrier such as selective distribution, physicochemical properties and the like, and the drugs can be slowly released by means of diffusion and the like, so that the purpose of safely and effectively treating diseases is achieved. However, the biocompatibility, biodegradability and safety restrict the use of some medicinal polymer materials, and the development of safe polymer materials with novel functions has been a hot spot in pharmaceutical research.
Nanoparticles having a core-shell structure can be formed by self-assembly of amphiphilic polymers in aqueous solution. Wherein the hydrophilic shell serves as a physical barrier preventing interaction between the nanoparticles, thereby ensuring stability of the nanoparticles; the hydrophobic core provides a storage of insoluble drugs by utilizing the lipophilic segment, thereby increasing the drug loading rate and realizing the function of protecting the drugs. Polyacrylic acid contains a large amount of carboxyl, has excellent hydrophilicity and biocompatibility, has the characteristic of easy modification, and is widely applied to the field of drug sustained release.
In the prior art, polyacrylic acid with pH responsiveness is grafted to a main bond of a hydrophobic polymer by a free radical polymerization method to obtain a pH sensitive polymer with a long grafted chain and the pH sensitive polymer is used for carrying medicine, so that the intelligent control release of the medicine is realized. However, the amphiphilic polymer obtained by the method, which takes the hydrophobic polymer as the main chain and takes the pH-responsive polyacrylic acid as the long-chain branch, is usually prepared by a free radical polymerization method, the preparation method is complicated, and the reaction process is difficult to control.
Disclosure of Invention
Aiming at the existing problems, the invention provides a modified polyacrylic acid copolymer and a preparation method and application thereof.
In order to achieve the technical purpose, the invention is specifically realized by the following technical scheme:
a modified polyacrylic acid copolymer, wherein the modified polyacrylic acid copolymer is represented by formula (I):
wherein m is 1 to 100, and n is 1 to 100.
In another aspect of the present invention, there is provided a method for preparing the modified polyacrylic acid copolymer, comprising the steps of: dissolving levo-pinitol, polyacrylic acid and a catalyst in an organic solvent, adding a coupling agent for sealing reaction under the nitrogen environment and at the temperature of 10 ℃, removing the solvent after the reaction is finished, and dialyzing with absolute ethyl alcohol to obtain a levo-pinitol grafted and modified polyacrylic acid copolymer;
wherein the structural formula of the levo-pinitol is shown as the formula (II):
further, the catalyst is selected from 4-dimethylamino pyridine, the organic solvent is a mixed solution of chloroform and tetrahydrofuran, and the coupling agent is selected from ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
Further, the sealing reaction by adding the coupling agent specifically comprises the following steps: after the reaction was carried out for 1 hour, the temperature was raised to 40 ℃ to carry out the reaction for 72 hours.
Further, the levo-pinitol is prepared by the following method: and (2) sequentially dropwise adding the tetrahydrofuran solution of the levopimaric acid and iodine into the tetrahydrofuran solution of the sodium borohydride at room temperature, taking the lower layer solution for rotary distillation, dissolving the obtained dope by using petroleum ether, taking the upper layer solution for liquid separation, taking the upper layer solution for dewatering, filtering to obtain filtrate, and carrying out rotary distillation to obtain the levopimaric alcohol shown in the formula (II).
In another aspect of the invention, the modified polyacrylic copolymer is also provided for use as a drug carrier.
The beneficial effects of the invention are as follows:
the levo-pinitol graft modified polyacrylic acid copolymer obtained by the one-step esterification method has good biocompatibility, amphipathy and adjustable pH responsiveness, and can be used for loading Chinese herbal medicines such as myricetin and the like and realizing drug release under different pH values.
Drawings
FIG. 1 is a transmission electron microscope image of levorotatory pimaric alcohol grafted polyacrylic acid micelle of the present invention;
FIG. 2 is a plot of L-pinitol grafted polyacrylic acid resonance light scattering intensity versus pH in accordance with the present invention;
FIG. 3 shows the release rate of myricetin loaded by levo-pimaric alcohol grafted polyacrylic copolymer of the present invention at different pH values.
Detailed Description
The technical solutions of the present invention will be described clearly and completely with reference to specific embodiments of the present invention, and it should be understood that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be obtained by a person skilled in the art without making any creative effort based on the embodiments in the present invention, belong to the protection scope of the present invention.
EXAMPLE 1 preparation of L-pinocenol
Adding 100ml tetrahydrofuran and 5.7g sodium borohydride into a 500ml three-neck flask, connecting a constant pressure dropping funnel and a spherical condenser tube, respectively dissolving 30.0g levopimaric acid and 25.3g iodine by tetrahydrofuran, respectively pouring into the constant pressure dropping funnel, introducing nitrogen, dropwise adding levopimaric acid solution at room temperature, dropwise adding iodine solution after completing dripping, reacting at room temperature for 1h, heating to 55 ℃, reacting for 12h, sequentially dropwise adding solutions prepared by 50ml absolute ethyl alcohol and 6.0g NaOH, after the reaction is stopped, retaining the lower layer solution, performing rotary distillation, dissolving the obtained sticky substance by petroleum ether, retaining the solution layer, transferring into a separating funnel, sequentially dissolving by Na 2 CO 3 Removing impurities with NaCl, hydrochloric acid and distilled water, keeping the upper layer, and removing impurities with anhydrous Na 2 SO 4 Dewatering, filtering to obtain filtrate, and rotary steaming to obtain levo-pinocenol.
EXAMPLE 2 preparation of Levolpimentol graft polyacrylic copolymer
Adding 5.8g of levopimanol, 1.4g of polyacrylic acid, 4.9g of 4-dimethylaminopyridine, 10mL of trichloromethane and 10mL of tetrahydrofuran into a three-neck flask, stirring and dissolving, introducing nitrogen, controlling the temperature to be 10 ℃, adding 4.0g of ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, sealing the device, heating to 40 ℃ after 1-hour reaction, removing the solvent by rotary evaporation after 72-hour reaction, dissolving with absolute ethanol, and dialyzing with absolute ethanol to obtain the levopimanol grafted polyacrylic acid copolymer.
Example 3
Dissolving the sample with DMEM medium, adjusting the concentration to 2mM, and filtering with a 0.22um filter; collecting L929 cells in logarithmic phase, counting cells, adjusting cell suspension concentration, plating on 96-well plate to obtain 50000 cells to be testedOne for each well. Adding sample solutions of L-pinocenol-grafted polyacrylic acid having final concentrations of 1,5, 10, and 15uM to the cells, respectively, 5% by weight of CO 2 After incubation for 24h at 37 ℃ the incubation was terminated and the well was carefully aspirated. After washing with PBS 2 times, 10. Mu.L of a medium containing 5mg/ml MTT was added and the incubation in the incubator was continued for 4 hours. Adding 150 μ L dimethyl sulfoxide (DMSO) into each well, and shaking on a shaking table at low speed for 10min to dissolve levo-pinitol grafted polyacrylic acid. The blank sample was used as a positive control, and the cell viability was measured by a full-wavelength plate reader (OD = 570). The specific data are shown in Table 1. As can be seen from Table 1, the relative cell survival rate is high, and the biocompatibility is good.
TABLE 1 toxic Effect of Levolpimentol grafted polyacrylic acid on L929 cells
Example 4
Placing the copper net plated with the carbon film in a surface dish covered with filter paper, then directly dripping the levo-pinitol grafted polyacrylic acid aqueous solution with the concentration of 1 mg/mL on the copper net, and drying the copper net for more than 24 hours for observation by a transmission electron microscope. The transmission electron microscope result is shown in fig. 1, and the result shows that the levo-terpineol grafted polyacrylic acid aqueous solution can form a micelle similar to a sphere, which indicates that the levo-terpineol grafted polypropylene has amphipathy.
Example 5
The levo-pimaric alcohol grafted polyacrylic acid is prepared into water solution with the concentration of 0.124mg/mL, and the pH value is adjusted by NaOH and hydrochloric acid to be 5.51,5.96,6.32, 6.71,7.14,7.46,7.96,8.4,9.57,9.93 and 10.28 respectively. And (3) measuring the change of the scattering strength of the levo-pinitol grafted polyacrylic acid along with the pH. The resonance light scattering was measured using a fluorescence spectrophotometer under the following conditions: the scanning speed is 200nm/min, the scanning wavelength is set to be 350-450nm, the temperature is set to be room temperature, the crack is set to be 2.5nm/2.5nm, the Delta lambda is set to be 0, and the scattering peak intensity at 390nm is taken as a graph. As can be seen from fig. 2, the change in the scattering intensity with the change in pH indicates that the stretched and crimped states of the molecular chain of the levopimaric alcohol-grafted polyacrylic acid change, that is, the levopimaric alcohol-grafted polyacrylic acid has pH responsiveness.
Example 6 Release conditions of Myricetin-loaded levopimaric alcohol-grafted polyacrylic acid copolymer micelles at different pHs
Taking a proper amount of myricetin-loaded levo-pinitol grafted polyacrylic acid copolymer micelle, wherein the content of myricetin is 20mg, adjusting the pH values to be 5.96,7.14,7.96,9.17 and 9.93 respectively, directly putting the myricetin-loaded levo-pinitol grafted polyacrylic acid copolymer micelle into a dissolution cup at the rotating speed of 100r/min, controlling the temperature of the dissolution liquid to be 37 +/-0.5 ℃, sampling 5mL at a preset time point, supplementing a release medium with the same volume and temperature, and testing for 24 hours. The sample was filtered through a 0.22 μm filter and the filtrate was taken as the test solution. The final cumulative release percentage is calculated by measuring myricetin in the sample by using a high performance liquid chromatograph. The release curves were plotted with the final cumulative release percentage on the ordinate and the pH on the abscissa, and the results are shown in fig. 3. As can be seen from fig. 3, the release rate of myricetin at different pH is different, and the release amount reaches the maximum at pH =8, which may reach 91%. The fact that the levo-pinoresinol grafted polyacrylic acid copolymer loaded myricetin can realize different drug release percentages under different pH values is shown.
Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (6)
1. A modified polyacrylic acid copolymer, wherein the modified polyacrylic acid copolymer is represented by formula (I):
wherein m is 1 to 100, and n is 1 to 100.
2. The method for preparing modified polyacrylic acid copolymer according to claim 1, wherein the levopimaric alcohol, the polyacrylic acid and the catalyst are dissolved in an organic solvent, the temperature is controlled at 10 ℃ in a nitrogen environment, a coupling agent is added for sealing reaction, the solvent is removed after the reaction is completed, and the levopimaric alcohol graft modified polyacrylic acid copolymer is obtained by dialysis with absolute ethyl alcohol;
wherein the structural formula of the levo-pinocenol is shown as the formula (II):
3. the method according to claim 2, wherein the catalyst is selected from 4-dimethylaminopyridine, the organic solvent is a mixed solution of chloroform and tetrahydrofuran, and the coupling agent is selected from ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride.
4. The preparation method according to claim 2, wherein the sealing reaction by adding the coupling agent specifically comprises: after the reaction was carried out for 1 hour, the temperature was raised to 40 ℃ to carry out the reaction for 72 hours.
5. The method of claim 2, wherein said levo-pinitol is prepared by the following steps: and (3) sequentially dropwise adding the tetrahydrofuran solution of the levopimaric acid and iodine into the tetrahydrofuran solution of the sodium borohydride at room temperature, taking the lower layer solution for rotary distillation, dissolving the obtained dope by using petroleum ether, taking the upper layer solution for liquid separation, taking the upper layer solution for dewatering, filtering to obtain filtrate, and carrying out rotary distillation to obtain the levopimaric alcohol in the formula (II).
6. Use of the modified polyacrylic copolymer of claim 1 as a pharmaceutical carrier.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900144A (en) * | 2006-07-14 | 2007-01-24 | 华东理工大学 | Poly propenoic acid/polypeptide grafted copolymer and its preparing method and use |
| CN103976948A (en) * | 2014-04-30 | 2014-08-13 | 成都市绿科华通科技有限公司 | Polymer medicament containing polyacrylic acid |
| CN104497217A (en) * | 2014-12-19 | 2015-04-08 | 新乡医学院 | Janus structure superparamagnetic nanoparticle and prepration method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1900144A (en) * | 2006-07-14 | 2007-01-24 | 华东理工大学 | Poly propenoic acid/polypeptide grafted copolymer and its preparing method and use |
| CN103976948A (en) * | 2014-04-30 | 2014-08-13 | 成都市绿科华通科技有限公司 | Polymer medicament containing polyacrylic acid |
| CN104497217A (en) * | 2014-12-19 | 2015-04-08 | 新乡医学院 | Janus structure superparamagnetic nanoparticle and prepration method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 具有三元菲环结构的脂环族二酐的合成、应用及其性能研究;李琴华等;《化工新型材料》;20101231;第38卷(第12期);第54-56页 * |
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